3. Introduction
• Motor neuron diseases include a variety of neurodegenerative
conditions that entirely or predominantly injure motor neurons
• Motor neuron diseases (MNDs) vs motor neuron disease (MND)
• Rare but incurable forms of neurodegenerative diseases
• In Ethiopia a study showed the prevalence to be 5/100,000
• Selectively affect the motor system
4. Why just Motor Neurons?
• Not clearly known
• Theories
▫ Motor neurons live longer, prone to d/t pathologies
▫ High energy expenditure
Large cells, large surface area to keep polarized
Have lots Membrane channels
Long axons(some >1meter) w/c travel long distance
5. • MNDs are classified according to
▫ Weather the loss of function is
Inherited( Autosomal dominant/recessive/x-linked)
Sporadic
• Weather the primary effects is on
• Upper motor neurons or/and Lower motor neurons
10. Primary Lateral Sclerosis(PLS)
• Rare variant, accounts for 2% to 4% of all cases of ALS
• Sclerosis of the lateral column( WM tract)
• Onset is in early 50s
• Pathological changes
▫ Loss of Betz cells in layer 5 of motor cortex
▫ Degeneration of the corticospinal tracts
• Very slowly progressive weakness, spasticity and pseudobulbar
palsy
11. PLS cont.
• Spasticity > weakness
• Mild cognitive impairment
• The diagnosis is clinical, after excluding structural causes
• Treatment
▫ No specific TX
▫ Ant-spasticity drugs (baclofen, tizanidine)
▫ TCAs, SSRIs, dextromethorphan/quinidine for Pseudobulbar affect
• Better prognosis than ALS
12. Hereditary spastic Paraparesis (Familial SP)
• Usually familial, autosomal dominant is the most common form
• 40% SPAST gene mutation
• Due to CST and posterior column degeneration
• Spastic paraparesis, spare craniobulbar function
• Clinically classified as Uncomplicated(pure) and complicated
• Treatment is symptomatic
13. Tropical Spastic Paraparsis
• HTLV-1 associated myelopathy
• Type 2 is endemic in Americans and Type 1 ( antigenically
different from Type 1) is common in Caribbean and Japan
• Melopatic feature(UMN signs, bladder dysfunction, sensory level)
• DX
▫ HTLV serology in blood and CSF, DNA PCR
▫ MRI- Periventricular WM T2 hyper intensity, thoracic cord atrophy
• No effective antiviral, Plasmapheresis have some effect
14. Plant Excitotoxins
• Neurolytrism
▫ Long-term ingestion of chickling
pea (Lathyrus sativus)
▫ Neurotoxin: β-N- oxalylamino-
l-alanine (BOAA), glutamate
agonist
▫ Degeneration of Betz cells and
the longest pyramidal tract to the
lower extremities
▫ Irreversible, acute- subacute
Spastic para/ quadriparesis,
Paresthesia and bladder
dysfunction
▫ Not progressive, unless there's
continuous use
17. Progressive Muscular Atrophy
• 5% to 8% of all adult-onset motor neuron diseases
• Younger age of onset than ALS, M>F
• Sporadic, some familial
• Asymmetric distal muscle atrophy of upper and lower extremities,
followed by bulbar and respiratory muscle involvement
• Dx- EMG(findings consistent with a widespread disorder of AHC)
• Treatment is same as ALS
18. Kennedy disease
• X- linked recessive
• CAG abnormal expansion in androgen receptor
protein, decrease the receptor function
• Slowly progressive limb girdle weakness, bulbar
dysfunction, cramps and fasciculation
• Gynecomastia, testicular atrophy, DM
• Dx- Abnormality of sex hormones, CAG repeats
• Treatment- symptomatic, enteral feeding,
genetic counseling
19. Spinal Muscular Atrophy ( SMA)
• Commonest MND of childhood; 1/10 000
• Autosomal recessive
• Caused by mutations in the SMN1 gene
• Degeneration is limited to the AHCs
• Lower limb predominant, symmetrical proximal weakness
• DX- EMG and NCS, Genetic study, Muscle biopsy
• TX- supportive and symptomatic, including surgical interventions
20.
21. Acute Poliomyelitis
• Acute LMN dysfunction
• Caused by Poliovirus, fecal-oral route
• 2-3% develop aseptic meningitis, 1% develop flaccid paralysis
• legs >>bulbar/respiratory muscles , asymmetrical flaccid
weakness
• Some functional improvement by 6 month((80%)
• Dx- EMG/NCS, CSF polio IgM, Culture (stool, nasopharynx), PCR
• Tx-supportive, PX- vaccination (the vaccine is 100% effective)
22. Postpolio Syndrome/PPMA
• In 28%- 64% of polio survivors
• Chronic nerve terminal sprouting
increase metabolic need and
chronic damage
• At least 10 years clinical stability
after acute poliomyelitis
• Fatigue, pain, myalgia, dysarthria,
dysphagia, sleep disturbance
• PPMA if there is Focal asymmetric
weakness and atrophy
• Diagnosis:
▫ Exclusion of other treatable
diseases
▫ EMG help to differentiate acute
from chronic
• Treatment is Symptomatic
24. Amyotrophic Lateral Sclerosis(ALS)
• Also called as
▫ Charcot's disease
▫ Motor neuron disease
▫ Lou Gerick disease
• The most common neurodegenerative disease
• The incidence is 2 -3 per 100,000
• The prevalence is 4-5 per 100,000
• More common in male
• Onset is late 50s-early 60s
25. ALS Cont.
• Amyotrophic- muscle wasting from LMN pathology
• Lateral Sclerosis- scarring and hardening of the lateral part of the spinal
cord
• It entirely or predominantly affect motor neuron
• Typically have a combination of UMN and LMN signs that affect multiple
segments of the body
26. • Pathology
▫ Loss of motor neuron cell bodies of
the motor cortex and anterior horns
of the spinal cord
▫ Signs of neuroinflammation
▫ Bunina bodies
▫ Cytoplasmic inclusions that contain
TDP-43, present in nearly all
patients with ALS, it’s pathologic link
b/n ALS and FTD
27. • Most cases(90%)are sporadic(SALS)
▫ Not clear but commonly seen among professional athletes, soccer players,
veterans, exposure to heavy metals,17 cyanotoxins,
▫ 60% have genetic bases
• Only 10% of cases are familial(FALS), autosomal dominant
▫ Mutation in C9orf72 gene are responsible for 30-40% of cases
▫ 20% are due to mutations in SOD1
28. • Genetics
▫ To date 43 genes, associated with ALS, have been identified
▫ 40% of familial and 10% sporadic cases are due mutation in C9orf72
gene, associated with FTD, or ALS-FTD
▫ 20% are due to mutations in SOD1( Limb onset ALS)
▫ 4% TARDBP ( linked to TDF 43 inclusions )
▫ <5% FUS( associated with early onset ALS)
29.
30. Pathophysiology
• The mechanisms underlying neurodegeneration in ALS are multifactorial,
inter-related molecular and genetic pathways.
▫ C9orf72 Mutations
▫ Impaired Protein Processing
▫ Impaired RNA Processing
▫ Cellular Abnormalities and Failure
▫ Immune Dysregulation/Inflammation
32. Clinical Presentation
• There are variety of phenotypes,
but they all share
▫ Progressive weakness/spasticity
▫ No equivalent pain/sensory loss
• 15% Can have only LMNL
• 4% can present with only UMNL
• Presentation
▫ 70% Limb onset
▫ 25 % Bulbar onset
▫ 4% Respiratory onset
▫ < 1% wasting and fasciculation
33.
34. • Muscle weakness begins in a focal area before involving contiguous muscles
in same region and then other region
▫ Begins in the legs as foot drop and, in the hands with difficulty of fine
movements
• Limb weakness :
▫ Progressive asymmetrical weakness
▫ Upper limb > lower limb
▫ Localized wasting
• Posterior neck muscle involvement
▫ Dropped head syndrome
35.
36. • Bulbar involvement with spastic and flaccid dysarthria is indicative of
ALS
• Pseudobulbar symptoms are very helpful sign for ALS
• Cramps over limb, trunk and neck
• Respiratory insufficiency from LMNLs is the common cause of death
• Cognitive Features- Executive dysfunction and Dementia (ALS-FTD)
40. Features arguing against ALS
• Lack of disease progression
• Pain, especially in the early stages
• Prominent sensory symptoms
• Symmetric findings
• Extrapyramidal features
• Early bowel/bladder dysfunction
• Ophtalmoplegia
41. • What causes selective vulnerability of certain motor neurons?
▫ CN 3, 4, 6 and Onuf motor nucleus are usually spared
▫ Not clearly known
▫ Regional difference in level of activity of calcium buffering system
▫ Difference in glutamate receptor subtype expression
42. Diagnostic workup
• Neurodiagnostic testing (Edx)
▫ NCS ( r/o MMN and
demyelinating lesions)
▫ EMG
▫ Neuromuscular ultrasound ( for
fasciculation's)
• Serology based on DDX
• Imaging( Brain, spinal)
• Genetic testing
• CSF for Neurofilaments
• Assessment for
• Pulmonary function testing
• Swallow studies
• Nutritional ass’ts
• Neuropsychiatric screening
• Speech evaluation
43. Edx
• NCS
• EMG- to establish evidence for Dx
▫ Active denervation
Fibrillation potential
Positive sharp waves
Fasciculation potentials
▫ Chronic reinnerviation
Large motor units and reduced recruitment
54. Summary
• ALS is the most common MNDs in adults
• In the absence of biological markers, ALS is primarily a
clinical diagnosis
• Electrodiagnostic studies extend the clinical findings by
revealing LMN changes, especially in muscles otherwise
regarded as unaffected
• Given the poor prognosis, ruling out alternative and
treatable diseases is as important as early diagnosis
55. Reference
• Bradley’s Neurology in Clinical Practice,7th edition
• Continuum 2020;Peripheral Nerve and Motor Neuron Disorders
• Up To Date online
• Harrison's principles of internal medicine, 20th edition
• Adam's and victor's principles of neurology, 11th edition
• Motor Neuron Diseases in Sub-Saharan Africa: The Need for More
Population-Based Studies
I will briefly discuss some of the common pure UMN and LMN diseases, and the combined form ALS, in a better detail
The term UMNDs include all disease conditions affecting UMN and LMNs in isolation or combination
But
The term motor neuron disease(MND) refer to a specific disorder of both upper and lower motor neurons, which is otherwise known as amyotrophic lateral sclerosis (ALS_.
Keeping the na/potassium gradient
Lot of surface area
Can be classified as
Usually caused by single gene mutation
In adults MNDs are usiually sporadic
The motor system has 2 parts, the UMN and the LMNs
Pathway of upper motor neuron from motor cortex to lower motor neuron in contralateral spinal cord.
(B) Representative sections through the cerebral cortex, pyramidal decussation, and spinal cord showing corticospinal tract.
The anatomical difference creates a specific feature for both with distinct C/F when lessoned
Why spasticity…..
Some conditions selectively affect the Upper or the lower motor neurons and disease like ALS affect both pathways
ALS…3rd type western pasfic ALS with or without parkin- dementia complex
still a debate wheather this is a dseparet intity or represent one end of a clinical spectrum of ALS
Reclassified as ALS, if develop LMNLs or fulfil criteria for ALS…
Atleast symptom duration of 4years is required for clinical dx
No , insignificant Muscle atrophy, No sensory disturba, No involuntary movement, No bowel or bladder incontinence/ late finding
The gray matter including the AHC unaffected
A very slowly evolving spastic paraparesis, Robotic gait……that spreads to the upper limbs and eventually causes pseudobulbar palsy
- Can be hemiplegic type (Mill type)
-Structural abnormalities (Chiari malformation, intrinsic /extrinsic cord lesions)
Myelopathies (MS, spondylotic myelopathy, HIV/HTLV1 myelopathy)
TX= symptom control and supportive care
Depending on the presence of other symptoms ,,,,,,,,,,,cxc-ed invo;vment…ms atrophy, Optic atropy, EPD, e-dementia, deafneas…
,
Different from PLS
-family hcx, onset infancy - 8th decade
- post column degeneration followed by loss of vibration and position sense..in 10-65%of cases
- cxced PNS/CNS invo;vment…ms atrophy, Optic atropy, EPD, e-dementia, deafnes…
Transmission is blood born
HTLV activated T cells and cytotoxic T cell mediated pathogenesis …max activityin the thoracic cotd
Young age of onset,………………Type 12 in IV drug abusers
Type 2 hiv coinfection
Common in our country
Neurotoxic myelopathy
IC Oxidative/reactive species …..impair mitochondrial phosphorylation
A sudden onset, somatosensory deficit, folloed by spastic weakness
cognitive impairment and neurodevelopmental delay reported
Cyanohydrin from the flour forms
Also cause tropical ataxic neuropaty
It has been questioned whether PMA is an independent disease or represents one end of the spectrum of ALS
If develop UMNs reclassified as ALS,,,,,,,,15% ALS initially present as PMA
Some data Older age of onset
Isolated loss of spinal motor neurons, Lateral column and all W.matters unaffected
Surgery to px scoliosis
4 tyeps based on Genetic study,
SMA 5…with weakness of distal than proximal involvement
Nowadays…live attenuated polio vaccine and non polio virus.. West nile virus
CSF- viral profile
- RNA PCR
EDx:
Low CMAPS
Normal SNAPs
Fibrillation potentials
weakness, usually in previously affected muscles
EMG is helpful to identify evidence of previous polio infection
TX…initially IVIG but has no mortality benefit
Adult onset NDDs
Atrophy of the interosseous muscles
Risk of ALS increases with age until the eighth decade,
It also affects thalamus,….
--Bunina bodies, small eosinophilic cytoplasmic inclusions found in the cytoplasm of surviving motor neurons
-cytoplasmic inclusions that contain transactive response DNA-binding protein 43 (TDP-43), which are present in nearly all patients with ALS
whether this is because of the sport activity, the genetic ability to participate in the sport, head or other trauma experienced during play, or other factors such as pesticides on the field.
In 1993, SOD1 mutations were the first genetic cause of familial ALS to be described
SOD1=
TDP-43= plays a critical role in RNA processing, and this pathway has become a central focus in the pathogenesis of ALS
e fused in sarcoma (FUS) gene
from time to time, incresing evidence of gene mutation in ALS
Strategies have evolved from individual gene mapping to increasingly powered technological and statistical methodologies. Since the implication of SOD1, 42 additional genes have been implicated in ALS to date with variable genetic support in replication and functional studies. GWAS, genome-wide association studies; WES, whole-exome sequencing; WGS, whole-genome sequencing
No single mechanism
C9orf72 protein function is not entirely elucidated, it appears to be related to membrane trafficking. Patients with expansions in the hexanucleotide repeat region of C9orf72 produce less mRNA and C9orf72 protein, produce less mRNA and C9orf72 protein, repeat region can produce multiple dipeptide repeat proteins that form cytosolic aggregations. Affect mRNA production
2. multiple mutant proteins associated with the development of ALS form potentially pathogenic intracellular aggregations, SOD1, the first gene associated with ALS, has a dominant negative effect likely due to the accumulation of misfolded mutant proteins with direct toxic effect on cellular function and indirect effects through impairment of cellular degradation of proteins, Aggregations of wild-type SOD1 protein have also been noted in patients with sporadic ALS
TDP-43 is a DNA/RNAbinding protein involved in transcription, RNA splicing, and transport and is usually exclusively located in the nucleus. The discovery of displaced cytoplasmic TDP-43 raised concern for either a loss of nuclear TDP-43 function in RNA processing or a toxic effect of TDP-43 cytoplasmic aggregates, s essential for axon stability and regeneration.
FUS is another RNA-binding protein associated with ALS, further supporting the notion of RNA processing as an important pathway in ALS neurodegeneration
Cellular Abnormalities and Failure, neuronal hyperexcitability, endoplasmic reticulum stress, mitochondrial failure, cytoskeletal abnormalities, impaired axonal transport, axonal retraction, and synaptic failure.
Immune Dysregulation/Inflammation, Clear evidence exists of immune activation in ALS and a relationship between proinflammatory states and faster disease progression.
The mechanisms underlying neurodegeneration in ALS are multifactorial and operate through inter-related molecular and genetic pathways. Specifically, neurodegeneration in ALS might result from a complex interaction of glutamate excitoxicity, generation of free radicals, cytoplasmic protein aggregates, SOD1 enzymes, combined with mitochondrial dysfunction, and disruption of axonal transport processes through accumulation of neurofilament intracellular aggregates. Mutations in TARDBP and FUS result in formation of intracellular aggregates, which are harmful to neurons. Activation of microglia results in secretion of proinflammatory cytokines, resulting in further toxicity. Ultimately, motor neuron degeneration occurs through activation of calcium-dependent enzymatic pathways. ALS=amyotrophic lateral sclerosis.
hetrogenous disease ‘-
UMN signs= loss of down going inhibition
LMNs= damage to the nerves, denervation
Myotomal weakness
History
Weakness of grip
Foot drop, trouble climbing stairs, My balance if off’
‘My arms feel heavy’
‘My tongue feels thick’
‘Rarely, cramps
The different variants of ALS
A. Proximal and symmetrical upper limb wasting (A) results in an inability to lift arms against gravity (“man-in-the-barrel” or flail-arm variant ALS).
B. Note the recessions above and below the scapular spine (B), indicating wasting of supraspinatus and infraspinatus muscles, as well as substantial loss of deltoid muscle. As a consequence, the glenohumeral joint becomes prominent, and prone to subluxation.
(C) Disproportionate wasting of the thenar muscles combined with the first dorsal interossei, the so-called “split-hand”, is a typical feature in ALS.17
Although the mechanisms underlying this disproportionate wasting of hand muscles are unclear, a corticomotoneuronal origin has been proposed.17
Specifically, the thenar muscles and first dorsal interossei receive more extensive corticospinal connections and thereby might be prone to glutamate-mediated excitotoxicity.18
(D) Substantial wasting of the tongue muscles in bulbar-onset ALS. Note the absence of palatal elevation present on vocalisation. Difficulty with mouth opening and dysphagia might require supplementary feeding through a percutaneous endoscopic gastrostomy. In further support of a corticomotoneuronal hypothesis, the tongue is often disproportionately affected in comparison to other oropharyngeal musculature in patients with bulbar-onset ALS. As with the thenar muscles in the hand, the tongue receives more extensive cortical input than other muscle groups in the oropharyngeal area
Dropped head
Claw hand
Foot drop
Based on the d/t patterns of involvement
Atypical features may occur later on
GLT-1 is affected
Thus the electrodiagnostic evaluation is not only useful in diagnosis, but is also helpful in monitoring progression of the disease, response to interventions, and in determining prognosis
in ALS= normal or only mildly reduced
Additional
Edx- verify denervation in weak muscles
abnormality in clinically uninvolved muscles
Pathophysiology of motor unit degeneration and reinnervation; with superimposition (C) of ten traces demonstrating the typically large, polyphasic, unstable (complex) motor units observed in established ALS (sweep duration 50 ms), with late components, indicating some re-innervation.
DX criteria
1. Spain
2. first revision in Virginia
3. Awaji iland Japan
EDX study based in symptomatic pts
These criteria divide the motor system into 4 anatomic regions: bulbar, cervical, thoracic, and lumbosacral.
Clinical evidence of UMN and LMN pathology is sought within each region; the certainty of diagnosis depends on how many regions reveal UMN and/or LMN pathology.
Five categories of certainty for the diagnosis were defined including: clinically definite, clinically probable, clinically probable with laboratory support, clinically possible, and clinically suspected ALS.2
For a diagnosis of clinically definite ALS, clinical evidence alone by the presence of both UMN and LMN signs was required in three of the four anatomic regions.2
However, the revised El Escorial criteria have been criticized for being too restrictive. In a population-based study, Traynor et al. found that 10% of 254 patients who died from ALS did not fulfill criteria beyond possible ALS, never reaching eligibility for clinical trial participation.45
in 2008. These criteria classify the certainty level of the diagnosis of ALS into one of three categories: clinically definite, probable, and possible (Figure 3). The category of “Laboratory Supported Probable ALS” became unnecessary based on the consensus panel's decision that clinical features of neurogenic change and neurogenic EMG findings should have the same diagnostic significance in an individual muscle, and can be considered together in a single limb to meet the required abnormalities for diagnosis of ALS. In addition, Fasicul. P were recognized as evidence of acute denervation and given equal significance to fibrillation and PSW potentials. The dialogue continues in the literature regarding the effect these changes have had on the timeliness of reaching diagnostic certainty; reports have been conflicting.46,47
With Awaji criteria.. Number of muscles with active denervation increased by 10%, and
20% of patients ipgraded from probable to definite ….under inx if it shortens the time to dx
Draw backs of the criterias
Pseudobulbar affect, cognitive impairments r not considered
Dx nomenclatures confuse pts, probable, possible, definite…
PLS for 4 years has aprotracted course
Barrier to enroll pts for clinical trail
There/ the Kings and Milano torino staging sytem
The ALSFRS-R measures 12 aspects of physical function, ranging from one’s ability to swallow and use utensils to climbing stairs and breathing. Each function is scored from 4 (normal) to 0 (no ability), with a maximum total score of 48 and a minimum total score of 0.
Follow up of disability progression
Downstream or upstream approaches to therapies
Riluzole and edaravone mechanism of actions. ,,,,,also explains Why is difficult to develop an effective drug ?
Molecular and cellular mechanism of therapeutic intervention and benefit afforded by riluzole ranging from anti-glutaminergic modulation of excitotoxic pathways, modulating low Ca2+ buffering capacity of motor neurons, mitochondrial membrane potential (ΔΨm), metabolism and function, effects on persistent sodium currents, depolarization of voltage dependent calcium channels and potentiation of calcium-dependent potassium currents whereas edaravone interventions asserts their benefits through redox mechanism and amelioration of reactive oxygen species (ROS). Depending on the disease stage riluzole might affect different therapeutic pathways at different stage and patients for example changes in excitotoxicity pathways might be an early transient effect, with other molecular and therapeutic pathways becoming more involved at later stage. Moreover, mitochondrial malfunction in MNs inhibits complex IV of the electron transport chain, which leads to ROS generation reversed by blocking ROS production by riluzole in MNs or by inhibition of Ca2+ efflux at synapse sites. Similarly, edaravone is a potent radical scavenger and removes oxygen radicals, including nitric oxide and peroxynitrite anion. Edaravone trap hydroxyl radical and quench active oxygen, suggesting its neuroprotective property against excitotoxicity and oxidative stress [Color figure can be viewed at wileyonlinelibrary.com]
For effective Rx
Emphasis should be given to never close the door for alternative dx even during follow-up of ALS pts
